Fungicidal compositions



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rat tii are 1 3,224,930 FUNGKIHDAL COMfOSlTIGNS William E. Burt, RoyalGait, Mich, assignor to Ethyl Corporation, New York, N.Y., a corporationof Virginia No Drawing. Filed Dec. 22, 1961, Ser. No. 161,384 4 Claims.(Cl. 167-22) This invention relates to fungicidal compositions, and moreparticularly, to fungicidally potent organochromium compounds and theiruse in combating fungi.

An object of this invention is to provide new fungicidal compositions.Still another object is to provide a new means for combating fungi. Afurther object is to provide new fungicidal compositions comprisingconditioning agents and certain organochromium compounds as describedherein.

The above and other objects are accomplished by the present inventionwhich resides in providing fungicidal compositions comprising aconditioning agent and as a principal active ingredient, a compoundhaving the formula:

wherein M is a metal of Group VIB of the Periodic Table according toMendeleev; R R R R and R are selected from the class consisting ofhydrogen and alkyl radicals having one to about 6 carbon atoms. and nand n are integers having the value one to six. Compounds of this typecan be prepared by reacting the corresponding triamine with eitherCr(CO) or cycloheptatriene chromium hexacarbonyl according to thegeneral method of Abel et al., J. Chem. Soc. (1959), 2323.

The most preferred metal is chromium. The fungicidally active compoundsof this invention are represented by diethylene triamine chromiumtricarbonyl and dihexylene triamine chromium tricarbonyl. However, othercompounds wherein the nitrogen atoms in the amine portion of themolecule are substituted with hydrocarbon radicals are also applicable.The preferred compounds either have no substituents on the nitrogenatoms or all the nitrogen atoms are substituted with identical radicals.These preferred compounds are illustrated by the compounds diethylenetriamine chromium tricarbonyl, pentaethylpropylene triamine chromiumtricarhonyl, dipropylene triamine chromium tricarbonyl, dibutylenetriamine chromium tricarbonyl, and the like. Further compounds whereinthe nitrogen atoms are substituted by hydrocarbon radicals can bearbitrarily divided into three subclasses. They are, as mentioned above,compounds wherein the nitrogen atoms are fully substituted; symmetricalderivatives wherein R is identical with R in the above formula, or whereR and R are equal to R and R and the third class of nitrogen substitutedcompounds of this invention are the unsymmetrical compounds wherein R isdifferent from R and R and R are either alike or different but notidentical with either R or R which again can be either alike ordifferent.

Fully substituted nitrogen derivatives have been illustrated above bythe compound pentaethyl ethylene triamine chromium tricarbonyl. Othercompounds of this class are pentamethyl propylene triamine chromiumtricarbonyl, and pentabutyl butylene triamine chromium tricarbonyl. Themost preferred compound is pentaethyl ethylene triamine chromiumtricarbonyl.

Symmetrical derivatives are illustrated by the compounds sym-trimethylethylene triamine chromium tricarbonyl, sym-dimethyl ethylene triaminechromium tricarbonyl and the like.

Unsymmetrical nitrogen substituted fungicidally active compounds areunsym-N-methyl, N-ethyl, propylene tri- 3,224,939 Patented Dec. 21, 1965amine chromium tricarbonyl, unsym-dimethylethylene triamme chromiumtricarbonyl and the like.

Because of its greater stability, the most preferred compound isdiethylene triamine. ch r qrpitup-trjgarbonyl Such compounds asdescribed above are useful in comhating fungi when they are applied tothe locus of the fungi. Such treatment, therefore, constitutes oneaspect of the invention. It has been found that the above materials areuseful in controlling and eliminating fungi which infest vegetables,animals and man. A facet of this invention is a novel method ofcombating and controlling fungi. Accordingly, one embodimnet of thisinvention is the method of combating fungi which comprises contactingthe fungus with a fungitoxic amount of a compound having the formulagiven above. Another aspect of this invention is the provision of amethod for controlling fungi which comprises treating matter suscepibleto fungal infestation with the compound of the above formula.

For maximum effectiveness, the active ingredient of the presentinvention is admixed in fungicidally effective amount with aconditioning agent of the type commonly referred to as a pest controlledadjuvant or modifier. Such adjuvants have been referred to by names suchas conditioning agent, dispersing agent, surface active agent, andsurface active dispersing agent. Their purpose is to extend the activeingredient to assure its efficacious penetration of, or application to,the locus being treated and to adapt the active ingredients for readyand efiicient application by using conventional equipment.

An advantage of using these conditioning agents is that the fungicidallyactive compounds may be too effective or too potent when used alone tobe of practical utility. Another advantage derived from the use of theseadjuvants is to permit field application by methods readily employed andstill obtain elfectively complete coverage of the material beingprotected.

Formulations of the fungicidally active ingredient with a suitableconditioning agent comprise both liquid and solid types as well as theaerosol type of formulation. y

The liquid type of formulation can have water, an organic solvent, or anoil-Water emulsion and the like as the conditioning agent.

It is also intended that the term conditioning agent include solidcarriers such as talc, attaclay, kieselguhr, chalk, diatomaceous earth,and the like, and various mineral powders, such as calcium carbonate,which act as a dispersant, as a carrier, and in some instances, performthe function of a surface active agent.

The conditioning agent may also be an industrial commodity such aspaint, raw polymer, finished plastic and the like. Such industrialmaterials act as a diluent, dispersant, wetting agent, and extender forthe active ingredient, thus, enhancing its fungicidal action.

The fomulations of this invention, therefore, comprise the above definedfungicidally active ingredient in a suitable material as a dispersant orconditioning agent. It is not intended that this invention be limited toany specific proportions of active ingredient and conditioning agent.The important feature of the invention is to provide a formulation ofsuch concentration that is appropriate for the desired application. Theconditioning agent will be present to provide the proper type of contactwith the material being protected.

Nor is it intended that the invention be limited to the use of afungicidally active ingredient in the presence of only a compound orproduct or material known as a conditioning agent. It has been foundthat other additives are useful in the preparation of the fungicidalpreparations. Other materials found useful are classified as adhesives.Spreading agents tend to increase the area found to be mostadvantageous.

ingredient formulations.

QID covered by a spray liquid. Many chemicals act as both wetting andspreading agents. Dried blood (blood albumin), sulfite lye, both in theliquid and dehydrated forms, and petroleum emulsions belong to thisgroup. Adhesives increase the adherence of the active agent to thetreated surface to augment resistance to wear and mechanical action.Bentonite and other clays, gelatin and glue, are examples of adhesives.

As mentioned previously, the fungicidal preparations are in the form ofeither liquid or dry or aerosol formulations. Liquid compositions,either solutions or dispersions, frequently also contain a surfaceactive dispersing agent in amounts suflicient to render the compositionreadily useful in aqueous spray application. The surface activedispersing agents referred to herein are sometimes known as wetting,dispersing or penetrating agents. They are agents which cause theformulations to be easily dispersed in water. They can be of theanionic, cationic, or nonionic type and include salts of long chainfatty acids, sulfonated oils, both vegetable and animal, petroleum oils,sulfates of long chain alcohols, phosphates of long chain alcohols,various polyethylene oxides, condensation products of ethylene oxidewith alcohol and phenols, quaternary ammonium salts, and the like. Thesurface active agent wil lusually be present to the extent of 0.1 topercent of the formulation. Typical of the liquid formulations is thewater solution or dispersion of the active ingredients. Example I below,is an example for the preparation of an aqueous suspension of a typicalactive ingredient described in this invention.

The active ingredients can also be dispersed or sus pended in variousorganic solvents such as alcohols, ketones, hydrocarbons, and petroleumfractions such as kerosene, dimethylformamide, and the like. In thesecases a surface active dispersing agent is usually present to provideready dispersability with water.

The solubility of the active ingredients of this invention in organicsolvents, furthermore, is such that they can be applied advantageouslyin the form of a solution in this type of solvent. In certain uses, thistype of vehicle is preferred, for example, in treating cloth, leather,or other fibrous articles. In these applications, it is preferred toapply the pesticides dissolved in a volatile solvent. After application,the volatile solvent evaporates leaving the fungicide impregnatedthroughout the surface of the article and in the dispersed form whichhas been Likewise, in applying the fungicides to smooth surfaces, as forexample in treating wood, a solution may be the most practical vehiclefor applying the protective film. Brushing, spraying, or dipping may bethe application method of choice. The choice of an appropriate solventis determined largely by the solubility of the active ingredients whichit is desired to employ, by the volatility required in the solvent, bythe spreading or flow characteristics thereof, and by the nature of thematerial being treated. Typical formulation of this type is described inExample II below.

Another typical formulation of the fungicidal ingredients is an oil inwater emulsion (see Example III). Generally these are prepared bydissolving the fungicidally active ingredient in an organic solvent,usually a petroleum fraction like kerosene, and then dispersing thissolution with vigorous agitation in a large volume of water containing aminor amount of a surface active agent.

In addition to the adjuvants and other ingredients described above, ithas been found that one can incorporate an adherent or sticking agentsuch as vegetable oils, naturally occurring gums, and other adhesives inthe active Likewise, humectants can be employed in the formulations.Furthermore, the formulations can be employed in admixture with otherpesticidal materials or other biocides such as insecticides, larvacides,bactericides, germicides, miticides or with other materials which it isdesired to apply along with the fungicides. In like manner, two or moreof the active ingredients may be formulated together in a singlecomposition, thus achieving control of a broader spectrum of fungi.

Fungicides can be applied in dry media as well as in liquid suspensionsor solutions. In fact, early practice in the art used dust formulationsalmost exclusively. It was only the advent of the introduction of spraymachinery that caused dust formulations to be considered with disfavor.However, it was soon realized that spraying was often not as convenientas dusting, particularly when large, comparatively inaccessiblecultivated fields are to be treated or when the area of interestnecessarily requires that it be treated with a dry agent. Dustformulations of my active compounds have a ready place in the art andindeed the use of these dry formulations should grow with time, sincethey are utilizable when treating large areas for fungicidal infestationby airplane dusting. Dusting is also extensively employed in treatingman and animals for fungicidal infestations.

A measure of the utility of the dust formulation is the impressiveamount of research which has been performed in this area. The particlesshape, the size, density and hardness, and the nature of the dry diluenthave been shown to be factors which are important as well as theabsorption and absorption characteristics thereof. Therefore, anotherdesired and efficacious formulation of the fungicidally activeingredient is a dust formulation which is prepared generally by millingthe active ingredient in ball mill within the presence of a drymaterial, for example, fullers earth. After milling, the mixture isscreened and the fraction passing through a very fine sieve iscollected. Thereafter, a further dilution is made by repeating the aboveprocedure with an additional very large amount of a compound such asfullers earth. Example IV exemplifies a dust formulation. A preferredformulation of the compounds comprises a wettable powder. In preparingwettable powders, several formulation procedures are possible (seeExample V for one type of procedure). It is one intention of thisinvention to provide compositions comprising the active ingredientdefined herein in combination with a minor amount of surface activeagent. Such surface active agents can be chosen for example from thosepreviously mentioned in connection with aqueous dispersion. Still othersurface active agents can be employed, the above merely showing arepresentative list of the more common material. Such formulations canbe readily admixed with a solid carrier. Formulations thus formed thencomprise the active ingredient of this invention, an inert carrier, anda surface active agent. Among the inert carriers which can be employedin preparing wettable powders are soya bean flour, tobacco flour, walnutshell flour, gypsum, mica, talc, apatite, pumice and the like. Inpreparing concentrated wettable powders it is preferred to employbetween 0.01 and 5 percent of the surface active agent, based upon theamount of active ingredient, and up to percent of the inert carrierbased upon the total amount of the formulation. Such concentratedformulations provide the advantage of permitting economical storage andtransportation of the fungicide and permit further dilution by simpleadmixture with water at the time of application.

The compounds described above are also active in colloidal formulations.A colloidal formulation is prepared by passing a mixture of the activeingredient, a hydrocarbon solvent and a large amount of water through acolloid mill until homogenation of the oil and water is achieved.Example VI gives an example of the preparation of a colloidalformulation.

The compounds also find effective use when formulated in aerosolformulations, i.e., when mixed with a liquid of low boiling point thatchanges to a gas when released from a confined space. Examples ofdiluent used in these formulations are fluorinated hydrocarbons such astetrafluoromethane, and hexafluoroethane. Mixed halogenated compoundscontaining fluorine and chlorine such as difiuorodichloromethane andpentafluorochloroethane and the like can also be used as the l quidhaving the necessary low boiling point. Other materials such as carbondioxide, sulfur dioxide, hydrogen sulfide and ammonia can be used, andof these, carbon dioxide generally is preferred. One method of preparingsuch aerosol formulations comprises introducing my new compounds into apressure cylinder and later introducing the liquifying diluent underpressure followed by mixing the cylinder to obtain uniform solution. Ifdesired, smaller containers can then be filled from the cylinder inwhich the formulation is prepared. In many cases it is desirable to adda second solvent to the low boiling material of the type described aboveso as to more readily dissolve my compounds. Examples of suchco-solvents are benzene, acetone, carbon tetrachloride and the like.Example VII is an example of the preparation of an aerosol typeformulation of my active ingredient.

My compounds are also elfective when formulated in an ointment fortopical application to the epidermis of animals and man. A typicalointment formulation is given in Example VIII below.

It i not intended that the finished formulations of my fungicidallyactive compounds be limited to any particular concentration range. Theconcentration range desired in my invention is that range necessary toaccomplish the desired end. A preferred range for agriculturalapplication is between 0.1 and 2,000 parts per million. Formulationscontaining as high as 30 percent active ingredient are used in treatinganimals and man. Typical formulations of this invention are described inthe following examples in which all parts are by weight.

The compounds in the following examples will have the designations givenbelow:

I. Diethylene triamine chromium tricarbonyl II. Sym.-N,N-dimethylethylene triamine chromium tricarbonyl III. N,N,N,N,N-pentamethyldiethylene triamine chromium tricarbonyl IV. Unsym.-N,N,N-trimethyldiethylene triamine chrmium tricarbonyl V. Diethylene triamine chromiumtricarbonyl VI. N-hexyl diethylene triamine chromium tricarbonyl VII.Sym.-N,N-dipentyl diethylene triamine chromium tricarbonyl VIII. N-ethyldiethylene triamine chromium tricarbonyl EXAMPLE I (WATER SUSPENSION) Aformulation of Compound I is prepared by adding, with vigorousagitation, 10 parts of this material to 1,000 parts of water containing1 part of Tween-80. This concentrated dispersion is further diluted1,000 times by the addition of Water to obtain a formulation of suitableconcentration for application. Thus, the resulting dispersion contains10 parts per million of my fungicide in the water dispersion.

EXAMPLE II (ORGANIC SOLUTION) A solution consisting of 5 parts ofCompound H in 250 parts of cyclohexanone is prepared by stirring the twoconstituents for a period of two minutes at a temperature of about 25 C.This concentrated solution suitable for storage or transportation isfurther diluted with 99,750 parts of kerosene to form a final dilutionof 50 p.p.m. suitable for application.

EXAMPLE III (OIL IN WATER EMULSION) An oil and water emulsion isprepared by dissolving parts of Compound III in 1,000 parts of kerosene.This solution is dispersed with vigorous agitation in 99,000 parts ofwater containing one part of Triton X- 100 to provide a dispersioncontaining 100 ppm. of active 1ngredient.

' USDA Circular No. 198, pages 12 and 14, 1931.

6 EXAMPLE IV (DUST FORMULATION) A dust formulation of the fungicide isprepared by adding one part of Compound IV to parts of fullers earth ina ball mill. The mixture is milled for a period of one hour, screened tocollect a fraction passing a 100 mesh sieve. This one percentformulation can be applied directly or further diluted. Further dilutionis made by repeating the above procedure with an additional 9,900 partsof fullers earth.

EXAMPLE V (WETTABLE POWDER) A mixture of 100 parts of Compound V, 1,000parts of attaclay and 0.01 part of Nacconol is intimately mixed in anL-shaped blender. The 10 percent wettable powder thus prepared producesa satisfactory water suspension when 11 parts are stirred into 10,000parts of water, producing a suspension containing 100 ppm. activeingredient.

EXAMPLE VI (COLLOIDAL FORMULATION) A colloidal formulation is preparedby passing a mix ture of 10 parts of Compound VI, 100 parts of kerosene,1000 parts of water and 1 part of mannitan monooleate through thecolloid mill until hom-ogenation of the oil in water is achieved.

EXAMPLE VII (AEROSOL FORMULATION) Into a cylinder rated at 100 p.s.i.working pressure, is introduced 10 parts of Compound VII. The cylinderis then made pressure tight except for one opening through which isintroduced a mixture of 10 parts acetone and 50 parts of dichlorodifluoromethane from a container at 2000 p.s.i. The cylinder into whichthe ingredients are introduced is then sealed off and inverted to give auniform aerosol solution of my active materials in the mixture ofco-solvents.

EXAMPLE VIII (OINTMENT) 2000 parts of Compound VIII is ground in a ballmill Agar-Plate Technique The compounds were screened for anti-fungalactivity by the Agar-Plate Technique against five fungi repre: sentinggroups of economic importance. The test fungl and their occurrences areas follows:

Aspelgillus nigerMildew of fabrics and leather, molding of fruit, bakerygood and stored grain. Penicillium expansumMolding of stored grain, hayand fruit. Alternaria solani-Early blight of potato and tomato.Glomerella cingulataBitter rot of apples. Trychophytoninterdigitale-Pathogenic for man and animals. Specifically, the methodwas the Agar-Plate Technic i f, e medium employed was Sabouraud DextroseAgar. This medium is used for carrying the stock cultures as well as forthe test itself. The agar is put into solutlon and then cooled to 42-45C. To this is added a saline spore suspension of the test organism. Theinoculated agar is then poured into sterile Petri dishes and allowed toharden. A suitable amount of the compound tested was placed on a onesquare centimenter area in the center of the agar. If the compound wassolid, the compound was sprinkled upon this area of the plate. When thecompound was a liquid, a depression was cut out in the center of theagar by means of a cork borer having a diameter of 1.5 mm. Four drops ofthe liquid compound were placed in this depression. The agar plates wereincubated for days at 25 C. If the compound is inhibitory, a zone ofclear agar will be noted around the area of inoculation. The size ofthis zone is measured, and is an indication of the inhibitory value ofthe compound tested. The diffusibility of the compound will affect thearea of inhibition. If the compound tested has no antifungicidalactivity, there will be no area of inhibition, and in some cases, growthwill appear under the compound tested.

Serial dilution tests The sample was tested for activity against thesame five fungi utilized in the Agar Plate Technique. The fungi for alltests were grown in a Bacto Sabouraud Liquid Medium, pH of 5.7. Thesample was dissolved in a minimal quantity of ethanol and diluted withsterile water thereafter to give an original concentration of 512 p.p.m.The test cultures were grown upon the Bacto Sabouraud Dextrose Agar fordays. A heavy spore suspension was prepared in buffered distilled water.The inoculum for each tube was one drop of the heavy spore suspension.The test cultures were incubated at 30 C. for 10 days. An effectiveconcentration of 250 parts per million (p.p.m.) is generally accepted asthe maximum concentration at which a chemical can be considered for useas an agricultural fungicide.

Further screening of representative types of these compounds was carriedout by the serial dilution test according to Burlingame and Reddish, J.Lab. Clin. Med. 24, page 765, 1939. The test fungi used in this casewere T richophyton interdigitale, T richophyton rubrum, T ryclzophytonschoenleinii, Microsporum audouini, Epidermophyton floccosum,Microsporum gypseum. These fungi were grown in Difcos Sabourauds liquidmedium, pH 4.7. Sample preparation consisted of dissolving aliquots ofeach compound in 10 mls. of ethanol and diluting to 512 p.p.m.concentrations with distilled water. These stock solutions were seriallydiluted through 10 tubes of culture medium. The inoculum consisted of 1drop per tube of a heavy spore suspension of the test fungi. The testswere incubated at 35 C. for one week.

Particular effectiveness of the samples in this series of testsindicates possible therapeutic use in the treatment of athletes foot,ringworm of the nails and scalp and external fungal infection ofanimals. Some presently commercial fungicides, utilized in this field oftherapy, contain an active ingredient in concentrations as high as 30percent by weight (300,000 parts per 1,000,000).

F oliar fungicide screening Ceral leaf rust wheat is grown in soil inpaper pots with 20-30 plants per pot. When the plants are 68 inchestall, they are sprayed with the test solutions (300 p.p.m. and 75 p.p.m.concentration) with three pots used for each treatment applied. Afterthe spray treatments have dried thoroughly, the plants are sprayed witha suspension of spores of wheat leaf rust disease, Paccinia rubz'govera,reared on live wheat leaf culture. After one week to ten days, diseasesymptoms are observed and percent control obtained by comparison of thesample With inoculated controls and manzate-treated positive controls.

Tomato late blight-Susceptible species tomato plants are treated fromseed and transplanted into soil in individual paper pots. When they are6 to 8 inches high, they are sprayed with the test solutions (300 p.p.m.and 75 p.p.m. concentration) with three plants used for each treatmentapplied. After the spray treatments have dried .thorou hly, the plantsare sprayed with a suspension of spores of the tomato late blightfungus, Phytophthora infestans, which is reared on lima bean agarculture. After a few days to one week disease symptoms are observed andpercent control obtained by comparison of the sample with inoculatedcontrols and manzate-treated positive controls.

Powdery mildew of cucumbers-Susceptible species oncumbers are grown insoil in paper pots with 2-3 plants per pot. When the first leaf hasreached a size of about 3 inches in diameter, they are sprayed with thetest solutions (300 p.p.m. and 75 p.p.m. concentration) with 3 pots usedfor each treatment applied. After the spray treatments have driedthoroughly, the plants are dusted with spores of powdery mildew fungusErysiphe cichoracearum, reared on live cucumber leaf culture. After oneweek to ten days, disease symptoms are observed and percent controlobtained by comparison of the sample with inoculated controls andKarathane-treated positive controls.

Agar plate Zone of inhibition in millimeters An Po As Ge Ti Diethylenetriamine chromium tricarbonyL. 5 5 3 3 2 No'rE.-An=Aspergillus niger.Pe=Pcnicillum ezpansum. As=

lltetniaria solani. Ge: Glomeralla cingulata. Ti=Trychophyton inter- Iclaim: 1. A fungicidal composition consisting of '(a) as a principalactive ingredient a compound having the formula N-orn-onz-N-orn-orn-None on wherein R and R are independently selected from the classconsisting of hydrogen and alkyl radicals having from one to six carbonatoms,

(b) from 0.1 to 5 weight percent of a surface active dispersing agent asa dispersant therefor, and

(c) the remainder of said composition consisting essentially of a solidcarrier selected from the class consisting of talc, attaclay,kieselguhr, chalk, diatoma- 'ceous earth, soybean fluor, tobacco fluor,walnut shell fluor, gypsum, mica, apatite, pumice and fullers earth.

2. A fungicidal composition of claim 1 wherein said principal activeingredient is diethylene triamine chromium tricarbonyl.

-3. Method of combating fungi comprising treating the locus of the fungiwith a fungitoxic amount of a compound having the formula wherein R andR are independently selected from the class consisting of hydrogen andalkyl radicals having one to six carbon atoms.

Method of combating fungi comprising treating the locus of the fungiwith a fungitoxic amount of a diethylene triamine chromium tricarbonyl.

References Cited by the Examiner UNITED STATES PATENTS 2,178,099 10/1939Gornitz et al. 260-431 2,208,253 7/ 1940 Flenner et al 167-22 2,278,9654/ 1942 Van Peski et a1 260-429 2,818,416 12/1957 Brown et al. 260-4292,818,417 12/1957 Brown et al. 260-429 2,839,552 6/1958 Shapiro et al260-429 2,864,843 12/1958 De Witt et al 26O--429.9 2,898,354 8/ 1959Shapiro et al. 260-429 2,916,503 -'l2/ 1959 Kozikowski 260-429 (Otherreferences on following page) 9 UNITED STATES PATENTS De Witt et a1.260-429 Brown et a1. 260-429 Gash 260-242 Shapiro et a1. 260-429 De Wittet a1 260-429 Weinmayer 260-439 Graham 260-439 Closson at al 260-429Sandel 23-14 Thomas 260-438" 1 0 3,032,570 5/1962 Haslam 260-42953,035,074 5/1962 Haven 260-439 OTHER REFERENCES 10 LEWIS GOTTS, PrimaryExaminer. MORRIS O. WOLK, Examiner.

1. A FUNGICIDAL COMPOSITION CONSISTING OF (A) AS A PRINCIPAL ACTIVEINGREDIENT A COMPOUND HAVING THE FORMULA